Identifying new insecticidal targets against Plasmodium falciparum infected Anopheles gambiae to fight malaria employing systems biology approaches

疟疾是一个重大的公共卫生问题，与撒哈拉以南国家的高死亡率、发病率和不适当的经济负担有关。最致命和最流行的疟疾形式是由血液传播的病原体恶性疟原虫引起的，其传播媒介是冈比亚按蚊。大多数方法遵循明显的战略，通过直接伤害寄生虫来抗击疟疾。然而，这伴随着严重的耐药性问题，迫切需要新的方法来控制疟疾。我们将走一条相当被忽视的路线。我们将通过针对媒介(An.冈比亚)，更具体地说，是媒介的感染形式。值得注意的是，在人类和动物模型中，关于微生物-宿主的相互作用，病原体和宿主经常相互制定耐受策略，这可能对病原体和宿主有利。病原体不是通过宿主免疫细胞清除病原体，而是穿透成骨细胞、肺或肝脏等宿主细胞，并诱导耐受机制，使宿主细胞和微生物得以存活。我们更希望干扰载体中的这种耐受机制，以诱导或撤销耐药机制。该项目的目的是开发和研究信号和新陈代谢的基因调控网络，以确定在感染恶性疟原虫的中肠内诱导免疫反应的关键基因。冈比亚，-寻找靶标，当靶向时，将重新编程载体中肠细胞的新陈代谢和信号调节，以增强对病原体的识别，从而诱导载体的免疫反应，并-通过实验验证这些预测。我们的目标是在载体中寻找药物靶标，当靶标时，将导致炎症性休克。这增加了整个生物体死亡的风险，或导致寄生虫清除。这两者都有利于减少疟疾的传播。为此，我们需要深入了解蚊子免疫反应的调节，特别是细胞如何将其蛋白质组织成相互作用的信号转导、调节和代谢途径。利用已报道的重建、自身发展和数据库中的途径信息，我们将研究构建信号、调节和代谢模型，并应用成熟的计算模型。我们将把实验中的基因表达数据整合到这些模型中，并模拟信号分子和酶功能的丧失，提出潜在的药物靶点，当靶点成为靶点时，重新编程联合系统。这些靶将通过函数微扰分析进行实验验证。到目前为止，还没有人研究过两者之间的相互作用。从系统的观点来看冈比亚的免疫反应和寄生虫，该项目将探讨这一问题，从而为具体的杀虫开发创造新的目标。

Malaria is a major public health problem associated with high mortality, morbidity rates and undue economic burden in sub-Saharan countries. The most fatal and prevalent form of malaria is caused by the blood-borne pathogen Plasmodium falciparum, whose transmitting vector is Anopheles gambiae. Most approaches follow the obvious strategy to fight malaria by harming the parasite directly. However, this comes along with severe resistance problems and there is the urgent need for new methods to control malaria. We will follow a rather neglected course. We will tackle malaria spread by targeting the vector (An. gambiae), and more specifically, the infected form of the vector. Strikingly, regarding microbial - host interactions in human and animal models, pathogens and the host often mutually develop tolerance strategies which can be beneficial for the pathogen and the host. Instead of a clearance of the pathogen by host immune cells, the pathogen penetrates host cells like osteoblasts, the lung or the liver and induces tolerance mechanisms that allow the host cell and the microorganism to survive. We want to rather interfere such tolerance mechanisms in the vector to induce or revoke resistance mechanisms. The aim of the project is to - develop and investigate gene regulatory networks for signaling and metabolism to identify genes being central for the induction of the immune response in the midgut of P. falciparum infected An. gambiae, - find targets which, when targeted, will reprogram regulation of metabolism and signaling of the vectors midgut cells to enhance the recognition of the pathogen and hence induction of the immune response of the vector, and- to experimentally validate these predictions.We aim to find drug targets in the vector which, when targeted, will induce an inflammatory shock. This increases the risk of death of the whole organism or leads to parasitic clearance. Both of which is beneficial for reducing the spread of malaria. For this, we need an in-depth understanding of the regulation of the immune response of the mosquitoes, and in particular how the cells organize their proteins into pathways of interacting signal transduction, regulation and metabolism. Using pathway information from reported reconstructions, own developments, and databases, we will investigate construct signaling, regulation and metabolic models, and apply well established computational models. We will integrate experimental gene expression data into these models and simulate loss of function of signaling molecules and enzymes coming up with potential drug targets reprogramming the joint system when targeted. These targets will be experimentally validated by functional perturbation assays. Until now, nobody has investigated the interplay between An. gambiaes immune response and the parasite on a systems view, which will be approached by this project leading to new targets for specific insecticidal development.